U.S. Pat. No. 5,192,753 states inter alia that dementia in human beings may be treated with compounds selected from the non-steroidal anti-inflammatory group of cyclooxygenase inhibitors. The non-steroid anti-inflammatory drugs (NSAIDs) referred to in U.S. Pat. No. 5,192,753 are all agents which possess significant ability to inhibit cyclooxygenase type 1 (COX-1). A number of publications have also occurred in the scientific literature which disclose that agents such as acetylacetic acid and indomethecin, which are generally viewed as potent inhibitors of COX-1, can be used in the treatment of Alzheimers disease; see for example:
McGeer et al, Lancet, 1990:335, 1037;
Rogers et al, Neurology, 1993:43; 1609-1611;
McGeer et al, Neurology, 1992:42, 447-449; and
Breitner et al, Neurology, 1994, 227-232.
Cyclooxygenase (COX) exists in the human as cyclooxygenase type I (COX-I) and cyclooxygenase type II (COX-II also referred to herein as COX-2). Hitherto there has been no suggestion that COX-II plays any role in Alzheimers disease. Indeed there has been no evidence which demonstrates that COX-II plays a part in any human central nervous system disorder. COX-II is inducilible by a number of agents such as mitogen, endotoxin, cytokines and the like but none of these agents which have been demonstrated as inducing COX-II have been shown to be causitive in Alzheimers disease.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor.
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. Although a wide range of COX-II inhibitors may be employed but it is preferred to employ compounds of the Formula I as set out hereinafter.
In one aspect the invention encompasses a method of treating a neurodegenerative disease in a human which comprises administering to said human an effective amount of a non-steroidal COX-2 inhibitor.
Within this apsect the invention encompasses a method of treating the neurodegenerative disease, Alzheimers Disease.
Within the above aspect the invention also encompasses a method of treating stroke, cerebral ischernia and de-myelinating disorders.
Oral administration (such as by tablet or capsule) is a preferred mode of administration
Within the above aspect, there is a preferred classs of method wherein the non-steroidal COX-2 inhibitor will bind at least 100 times as well to COX-2 as to COX-1.
Within the above aspect there is a preferred class of COX-2 inhibitors, which is:
(a) 3-(4-(Aminosulfonyl) phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,
(b) 3-(4-(Aminosulfonyl) phenyl)-2-(4-fluorophenyl)thiophene,
(c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,
(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,
(e) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl) thiophene-2-carboxylic acid,
(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole,
(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one
(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole,
(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone,
(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl) furan,
(l) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl) thiophene,
(n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,
(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(p) 5,5-Dimethyl-3-(3fluorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, and
(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
The invention also encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases 
or pharmaceutically acceptable salts thereof wherein:
X-Y-Z-is selected from the group consisting of:
(a) xe2x80x94CH2CH2CH2xe2x80x94,
(b) xe2x80x94C(O)CH2CH2xe2x80x94,
(c) xe2x80x94CH2CH2C(O)xe2x80x94,
(d) xe2x80x94CR5(R5xe2x80x2)xe2x80x94Oxe2x80x94C(O)xe2x80x94,
(e) xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5xe2x80x2)xe2x80x94,
(f) xe2x80x94CH2xe2x80x94NR3xe2x80x94CH2xe2x80x94,
(g) xe2x80x94CR5(R5xe2x80x2)xe2x80x94NR3xe2x80x94C(O)xe2x80x94,
(h) xe2x80x94CR4=CR4xe2x80x2xe2x80x94Sxe2x80x94,
(i) xe2x80x94Sxe2x80x94CR4xe2x95x90CR4xe2x80x2xe2x80x94,
(j) xe2x80x94Sxe2x80x94Nxe2x95x90CHxe2x80x94,
(k) xe2x80x94CH⊚Nxe2x80x94Sxe2x80x94,
(l) xe2x80x94Nxe2x95x90CR4xe2x80x94Oxe2x80x94,
(m) xe2x80x94Oxe2x80x94CR4xe2x95x90Nxe2x80x94
(n) xe2x80x94Nxe2x95x90CR4xe2x80x94NHxe2x80x94;
(o) xe2x80x94Nxe2x95x90CR4xe2x80x94Sxe2x80x94, and
(p) xe2x80x94Sxe2x80x94CR4xe2x95x90Nxe2x80x94;
(q) xe2x80x94C(O)xe2x80x94NR3xe2x80x94CR5(R5xe2x80x2)xe2x80x94;
(r) xe2x80x94R3Nxe2x80x94CHxe2x95x90CHxe2x80x94 provided R1 is not xe2x80x94S(O)2Me
(s) xe2x80x94CHxe2x95x90CHxe2x80x94NR3xe2x80x94 provided R1 is not xe2x80x94S(O)2Me
when side b is a double bond, and sides a an c are single bonds; and
X-Y-Z-is selected from the group consisting of:
(a) xe2x95x90CHxe2x80x94Oxe2x80x94CHxe2x95x90, and
(b) xe2x95x90CHxe2x80x94NR3xe2x80x94CHxe2x95x90,
(c) xe2x95x90Nxe2x80x94Sxe2x80x94CHxe2x95x90,
(d) xe2x95x90CHxe2x80x94Sxe2x80x94Nxe2x95x90,
(e) xe2x95x90Nxe2x80x94Oxe2x80x94CHxe2x95x90,
(f) xe2x95x90CHxe2x80x94Oxe2x80x94Nxe2x95x90,
(g) xe2x95x90Nxe2x80x94Sxe2x80x94Nxe2x95x90,
(h) xe2x95x90Nxe2x80x94Oxe2x80x94Nxe2x95x90,
when sides a and c are double bonds and side b is a single bond;
R1 is selected from the group consisting of
(a) S(O)2CH3,
(b) S(O)2NH2,
(c) S(O)2NHC(O)CF3,
(d) S(O)H)CH3,
(e) S(O)(NH)NH2,
(f) S(O)(NH)NHC(O)CF3,
(g) P(O)(CH3)OH, and
(h) P(O)(CH3)NH2,
R2 is selected from the group consisting of
(a) C1-6alkyl,
(b) C3, C4, C5, C6, and C7, cyloalkyl,
(c) mono-, di- or tri-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo,
(3) C1-6alkoxy,
(4) C1-6alkylthio,
(5) CN,
(6) CF3,
(7) C1-6alkyl,
(8) N3,
(9) xe2x80x94CO2H,
(10) xe2x80x94CO2xe2x80x94C1-4alkyl,
(11) xe2x80x94C(R5)(R6)xe2x80x94OH,
(12) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl, and
(13) xe2x80x94C1-6alkylxe2x80x94CO2xe2x80x94R5;
(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of
(1) hydrogen,
(2) halo, including fluoro, chloro, bromo and iodo,
(3) C1-6alkyl,
(4) C1-6alkoxy,
(5) C1-6alkylthio,
(6) CN,
(7) CF3,
(8) N3,
(9) xe2x80x94C(R5)(R6)xe2x80x94OH, and
(10) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R3 is selected from the group consisting of
(a) hydrogen,
(b) CF3,
(c) CN,
(d) C1-6alkyl,
(e) hydroxyC1-6alkyl,
(f) xe2x80x94C(O)xe2x80x94C1-6alkyl,
(g) optionally substituted
(1) xe2x80x94C1-5 alkyl-Q,
(2) xe2x80x94C1-3alkylxe2x80x94Oxe2x80x94C1-3 alkylxe2x80x94Q,
(3) xe2x80x94C1-3 alkylxe2x80x94Sxe2x80x94C1-3 alkylxe2x80x94Q,
(4) xe2x80x94C1-5 alkylxe2x80x94Oxe2x80x94Q, or
(5) xe2x80x94C1-5 alkylxe2x80x94Sxe2x80x94Q,
wherein the substituent resides on the alkyl and the substituent is C1-3alkyl;
(h) xe2x80x94Q
R4 and R4xe2x80x2 are each independently selected from the group consisting of
(a) hydrogen,
(b) CF3,
(c) CN,
(d) C1-6alkyl,
(e) xe2x80x94Q,
(f) xe2x80x94Oxe2x80x94Q;
(g) xe2x80x94Sxe2x80x94Q, and
(h) optionally substituted
(1) xe2x80x94C1-5 alkylxe2x80x94Q,
(2) xe2x80x94Oxe2x80x94C1-5 alkylxe2x80x94Q,
(3) xe2x80x94Sxe2x80x94C1-5 alkylxe2x80x94Q,
(4) xe2x80x94C1-3alkylxe2x80x94Oxe2x80x94C1-3alkylxe2x80x94Q,
(5) xe2x80x94C1-3alkylxe2x80x94Sxe2x80x94C1-3alkylxe2x80x94Q,
(6) xe2x80x94C1-5 alkylxe2x80x94Oxe2x80x94Q,
(7) xe2x80x94C1-5 alkylxe2x80x94S""Q,
wherein the substituent resides on the alkyl and the substituent is C1-3alkyl, and
R5, R5xe2x80x2, R6, R7 and R8 are each independently selected from the group consisting of
(a) hydrogen,
(b) C1-6alkyl,
or R5 and R6 or R7 and R8 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or7 atoms;
Q is CO2H, CO2xe2x80x94C1-4alkyl, tetrazolyl-5-yl, C(R7)(R8)(OH), or C(R7)(R8)(Oxe2x80x94C1-4alkyl);
provided that when Xxe2x80x94Yxe2x80x94Z is xe2x80x94Sxe2x80x94CR4xe2x95x90CR4xe2x80x2, then R4 and R4xe2x80x2 are other than CF3.
One Class within this embodiment are the compounds of formula I 
or pharmaceutically acceptable salts thereof wherein:
Xxe2x80x94Yxe2x80x94Zxe2x80x94 is selected from the group consisting of xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5xe2x80x2)xe2x80x94 when side b is a double bond, and sides a and c are single bonds; and
R1 is selected from the group consisting of
(a) S(O)2CH3,
(b) S(O)2NH2,
R2 is selected from the group consisting of
(a) C1-6alkyl,
(b) C3, C4, C5, C6, and C7, cycloalkyl,
(c) heteroaryl
(d) benzoheteroaryl
(e) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo,
(3) C1-6alkoxy,
(4) C1-6alkylthio,
(5) CN,
(6) CF3,
(7) C1-6alkyl,
(8) N3,
(9) xe2x80x94CO2H,
(10) xe2x80x94CO2xe2x80x94C1-4alkyl,
(11) xe2x80x94C(R5)(R6)xe2x80x94OH,
(12) xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94C1-4alkyl, and
(13) xe2x80x94C1-6alkylxe2x80x94CO2xe2x80x94R5;
R5, R5xe2x80x2 and R6 are each independently selected from the group consisting of
(a) hydrogen,
(b) C1-6alkyl,
or R5 and R6 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with C1-6alkyl including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, C1-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, C1-6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies xe2x80x94SCH2CH2CH3.
Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
Benzoheteroaryl includes the above heteroaryl rings to which it is possible to fuse a benzene ring.
Exemplifying the invention are:
(a) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,
(b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,
(c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,
(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,
(e) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid,
(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole,
(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one
(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole,
(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone,
(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan,
(1) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene, and
(n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,
(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(p) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(w) 3 -(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl)phenyl)-b 2-(5H)-furanone,
(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
In a second embodiment, the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.
Within this embodiment the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.
In a third embodiment, the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
For purposes of this specification a compound is said to selectively inhibit COX-2 in preference to COX-1 if the ratio of the IC50 concentration for COX-1 inhibition to COX-2 inhibition is 100 or greater.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamnine, diethylamnine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolarnine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The Compound of Formula I is useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. Compounds of formula I may also be useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer Disease (ie Alzheimer""s dementia).
Compounds of formula I will also be useful in the treatment of Stroke, cerebral ischemia and de-myelinating disorders.
Compounds of formula I will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
By virtue of its high cyclooxygenase-2 (COX-2) activity and/or its selectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1) as defined above, compounds of formula I will prove useful as an alternative to conventional non-steroidal antiinflammatory drugs (NSAID""S) particularly where such non-steroidal antiinflammatory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems (including those relating to reduced or impaired platelet function); kidney disease (eg impaired renal function); those prior to surgery or taking anticoagulants; and those susceptable to NSAID induced asthma.
Similarly, compounds of formula I, will be useful as a partial or complete substitute for conventional NSAID""S in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetominophen or phenacetin; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or non-sedating antihistamine. In addition the invention encompasses a method of treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effect amount of the compound of Formula I, optionally co-administered with one or more ofsuch ingredients as listed immediately above.
Compounds of the present invention are inhibitors of cyclooxygenase-2 and are thereby useful in the treatment of cyclooxygenase-2 mediated diseases as enumerated above. This activity is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a compound of formula I. The IC50 values represent the concentration of inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control. Illustrating this aspect, we have found that the Compounds of the Examples are more than 100 times more effective in inhibiting COX-2 than they are at inhibiting COX-1. In addition they all have a COX-2 IC50 of 1 nM to 1 mM. By way of comparison, Ibuprofen has an IC50 for COX-2 of 1 mM, and Indomethacin has an IC50 for COX-2 of approximately 100 nM. For the treatment of any of these cyclooxygenase mediated diseases, compounds of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.
As indicated above, pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc:, containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor.
From another aspect this invention provides the use of a COX-II inhibitor in the manufacture of a medicament for the treatment of neurodegenerative diseases including dementia, and in particular Alzheimers disease. Risk factors include those based on Apo lipoprotein genotype, age, Mild Cognitive Impairment and family History.
When used herein the term xe2x80x9ctreatingxe2x80x9d includes treatment of existing disease and prophylactic treatment of those at risk of developing the disease.
When used herein the term xe2x80x9cCOX-IIxe2x80x9d inhibitor means a compound able to inhibit human COX-II enzyme without causing relatively significant inhibition of human COX-I enzyme. Generally compounds which bind at least 10 times as well to COX-I receptors as to COX-II receptors (ie will have a IC50 COX-II receptor only one tenth the numerical value of the COX-I receptor) are chosen for use in the invention, more aptly 20 times as well, favourably 50 times as well most favourably at least 100 times as well, and preferably at least 10.00 times as well.
The COX-II inhibitors for use in this invention are most aptly those which are highly brain penetrant so that the maximum concentration of COX-II inhibitor after administration of the anti-neurodegenerative for example the anti-alzheimer effective dose of COX-II inhibitor is at least the binding IC50 value and preferably at least 10 times that value for example at least 100 times the binding IC50 value.
The COX-II inhibitor may be of any structural type other than a steroid. However, most aptly the COX-II inhibitor employed in this invention is not a carboxylic acid or a salt thereof. Most favourably it will possess a SO2CH3, NHSO2CH3, SO2NH2, SO2CHCH3 or like substituent on an aromatic ring especially on a phenyl ring.
Our investigations and statements made in the more recent of the following patents indicate that COX-II inhibitors may be found in U.S. Pat. Nos 4,375,479; 4,590,205; 4,820,827; 5,343,991; EP 0418845; WO 91/19708; WO 94/15932 and WO 94/13635. Each of the above documents is incorporated herein by cross reference.
Thus in one aspect this invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a patient therapeutically effective amount of a compound generically disclosed (and preferably a compound specifically described) in U.S. Pat. Nos. 4,375,479; 4,590,205; 4,820,827; 5,344,991; EP 0418845; WO 91/19708; WO 94/15932 or WO 94/13635 all of which are incorporated herein by cross reference.
The invention also provides the use of such compounds in the manufacture of a medicament for the treatment of neurodegenerative disease and in particular Alzheimers disease.
Favourably the COX-II inhibitor employed is one described in WO 94/26731 (published Nov. 24, 1994), WO 94/20480 (published Sep. 15, 1994), U.S. Pat. No. 5,436,265 (issued Jul. 25, 1995), WO 95/00501 (published Jan. 5, 1995) or WO 95/18799 (published Jul. 13, 1995) all of which are incorporated herein by cross reference.
The medicaments for treating neurodegenerative disease may be formulated as described in the aforementioned referenced documents. The medicament may be employed in the doses and regimens set out in the aforementioned referenced documents with respect to the treatment of diseases which benefit from the administration of a COX-II inhibitor.
It is a great advantage of this invention that treatment may be carried out without causing gastric side effects of the type that can occur when COX I inhibitors are used for prolonged periods. Since neurodegenerative diseases such as Alzheimers disease are generally progressive treatment may need to take place for a number of years. Thus the provision of medicaments which are surprisingly effective without any significant tendency to cause gastric side effects at the therapeutic dose is of great use particularly to the elderly. The use of medicaments of this invention for the treatment of patients who are asymptotic is also envisaged especially in those cases where genetic information suggests that the patient is likely to develop Alzheimers disease or other neurodegenerative disease especially those which may be termed dementia, for example senile dementia or pre-senile dementia.
Favourably this invention provides a method of treating neurodegenerative disease without any significant tendency to cause gastric side effects which comprises the oral administration of a pharmaceutical composition which comprises an effective amount of a COX-II inhibitor and a pharmaceutical acceptable carrier therefor.
Such a method is applicable to patients with overt symptoms of disease and is applicable without overt symptoms of the disease (asymptotic patients).
Generally the oral dosage form will be administered from 1 to 6 times per day. Preferably the oral dosage form will be administered once or twice per day.